EP3698779A1 - Nachweis und verwendung niedermolekularer modulatoren des kälte-menthol-rezeptors trpm8 - Google Patents
Nachweis und verwendung niedermolekularer modulatoren des kälte-menthol-rezeptors trpm8 Download PDFInfo
- Publication number
- EP3698779A1 EP3698779A1 EP19214768.4A EP19214768A EP3698779A1 EP 3698779 A1 EP3698779 A1 EP 3698779A1 EP 19214768 A EP19214768 A EP 19214768A EP 3698779 A1 EP3698779 A1 EP 3698779A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- modulator
- trpm8
- receptor
- compound
- cold
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 229940041616 menthol Drugs 0.000 title claims abstract description 17
- 238000001514 detection method Methods 0.000 title description 2
- 101150111302 Trpm8 gene Proteins 0.000 claims abstract description 53
- 102000003610 TRPM8 Human genes 0.000 claims abstract description 51
- 238000000034 method Methods 0.000 claims abstract description 12
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 35
- 238000012360 testing method Methods 0.000 claims description 19
- 102000005962 receptors Human genes 0.000 claims description 18
- 108020003175 receptors Proteins 0.000 claims description 18
- 230000000694 effects Effects 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 101100047459 Homo sapiens TRPM8 gene Proteins 0.000 claims description 9
- 239000004753 textile Substances 0.000 claims description 9
- 230000001939 inductive effect Effects 0.000 claims description 8
- 239000005022 packaging material Substances 0.000 claims description 8
- 230000001413 cellular effect Effects 0.000 claims description 7
- 239000002917 insecticide Substances 0.000 claims description 7
- 239000002324 mouth wash Substances 0.000 claims description 7
- 230000001270 agonistic effect Effects 0.000 claims description 6
- 239000006071 cream Substances 0.000 claims description 6
- 239000000077 insect repellent Substances 0.000 claims description 6
- 229940051866 mouthwash Drugs 0.000 claims description 6
- 239000008177 pharmaceutical agent Substances 0.000 claims description 6
- 241000195940 Bryophyta Species 0.000 claims description 5
- 235000011929 mousse Nutrition 0.000 claims description 5
- 239000002453 shampoo Substances 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 241000282412 Homo Species 0.000 claims description 4
- 208000002193 Pain Diseases 0.000 claims description 4
- 235000013305 food Nutrition 0.000 claims description 4
- 238000000338 in vitro Methods 0.000 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 4
- 239000006210 lotion Substances 0.000 claims description 4
- 241001465754 Metazoa Species 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 206010042496 Sunburn Diseases 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940112822 chewing gum Drugs 0.000 claims description 3
- 235000015218 chewing gum Nutrition 0.000 claims description 3
- 235000009508 confectionery Nutrition 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 235000015243 ice cream Nutrition 0.000 claims description 3
- 230000010220 ion permeability Effects 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000004806 packaging method and process Methods 0.000 claims description 3
- 229940124641 pain reliever Drugs 0.000 claims description 3
- 230000035699 permeability Effects 0.000 claims description 3
- 201000001514 prostate carcinoma Diseases 0.000 claims description 3
- 239000000516 sunscreening agent Substances 0.000 claims description 3
- 239000000606 toothpaste Substances 0.000 claims description 3
- 229940034610 toothpaste Drugs 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 230000006698 induction Effects 0.000 claims description 2
- 239000000470 constituent Substances 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 20
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 18
- 239000000126 substance Substances 0.000 description 15
- 239000011575 calcium Substances 0.000 description 13
- 239000000556 agonist Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- RCEFMOGVOYEGJN-UHFFFAOYSA-N 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-1,4-dihydropyrimidin-2-one Chemical compound OC1=CC=CC=C1N1C(=O)NC(C=2C=C(C=CC=2)[N+]([O-])=O)=CC1 RCEFMOGVOYEGJN-UHFFFAOYSA-N 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000004098 Tetracycline Substances 0.000 description 4
- 230000003042 antagnostic effect Effects 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 229960002180 tetracycline Drugs 0.000 description 4
- 229930101283 tetracycline Natural products 0.000 description 4
- 235000019364 tetracycline Nutrition 0.000 description 4
- 150000003522 tetracyclines Chemical class 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
- GRRNUXAQVGOGFE-UHFFFAOYSA-N Hygromycin-B Natural products OC1C(NC)CC(N)C(O)C1OC1C2OC3(C(C(O)C(O)C(C(N)CO)O3)O)OC2C(O)C(CO)O1 GRRNUXAQVGOGFE-UHFFFAOYSA-N 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- 229930182816 L-glutamine Natural products 0.000 description 3
- 229930189065 blasticidin Natural products 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 102000045979 human TRPM8 Human genes 0.000 description 3
- GRRNUXAQVGOGFE-NZSRVPFOSA-N hygromycin B Chemical compound O[C@@H]1[C@@H](NC)C[C@@H](N)[C@H](O)[C@H]1O[C@H]1[C@H]2O[C@@]3([C@@H]([C@@H](O)[C@@H](O)[C@@H](C(N)CO)O3)O)O[C@H]2[C@@H](O)[C@@H](CO)O1 GRRNUXAQVGOGFE-NZSRVPFOSA-N 0.000 description 3
- 229940097277 hygromycin b Drugs 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 125000005647 linker group Chemical group 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 125000006850 spacer group Chemical group 0.000 description 3
- NFLGAXVYCFJBMK-RKDXNWHRSA-N (+)-isomenthone Natural products CC(C)[C@H]1CC[C@@H](C)CC1=O NFLGAXVYCFJBMK-RKDXNWHRSA-N 0.000 description 2
- BKZOUCVNTCLNFF-IGXZVFLKSA-N (2s)-2-[(2r,3r,4s,5r,6s)-2-hydroxy-6-[(1s)-1-[(2s,5r,7s,8r,9s)-2-[(2r,5s)-5-[(2r,3s,4r,5r)-5-[(2s,3s,4s,5r,6s)-6-hydroxy-4-methoxy-3,5,6-trimethyloxan-2-yl]-4-methoxy-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-7-methoxy-2,8-dimethyl-1,10-dioxaspiro[4.5]dec Chemical compound O([C@@H]1[C@@H]2O[C@H]([C@@H](C)[C@H]2OC)[C@@]2(C)O[C@H](CC2)[C@@]2(C)O[C@]3(O[C@@H]([C@H](C)[C@@H](OC)C3)[C@@H](C)[C@@H]3[C@@H]([C@H](OC)[C@@H](C)[C@](O)([C@H](C)C(O)=O)O3)C)CC2)[C@](C)(O)[C@H](C)[C@@H](OC)[C@@H]1C BKZOUCVNTCLNFF-IGXZVFLKSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VUNOFAIHSALQQH-UHFFFAOYSA-N Ethyl menthane carboxamide Chemical compound CCNC(=O)C1CC(C)CCC1C(C)C VUNOFAIHSALQQH-UHFFFAOYSA-N 0.000 description 2
- 206010016326 Feeling cold Diseases 0.000 description 2
- OUVXYXNWSVIOSJ-UHFFFAOYSA-N Fluo-4 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C2=C3C=C(F)C(=O)C=C3OC3=CC(O)=C(F)C=C32)N(CC(O)=O)CC(O)=O)=C1 OUVXYXNWSVIOSJ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 102000004310 Ion Channels Human genes 0.000 description 2
- 108090000862 Ion Channels Proteins 0.000 description 2
- BKZOUCVNTCLNFF-UHFFFAOYSA-N Lonomycin Natural products COC1C(C)C(C2(C)OC(CC2)C2(C)OC3(OC(C(C)C(OC)C3)C(C)C3C(C(OC)C(C)C(O)(C(C)C(O)=O)O3)C)CC2)OC1C1OC(C)(O)C(C)C(OC)C1C BKZOUCVNTCLNFF-UHFFFAOYSA-N 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102100034030 Transient receptor potential cation channel subfamily M member 8 Human genes 0.000 description 2
- QOMNQGZXFYNBNG-UHFFFAOYSA-N acetyloxymethyl 2-[2-[2-[5-[3-(acetyloxymethoxy)-2,7-difluoro-6-oxoxanthen-9-yl]-2-[bis[2-(acetyloxymethoxy)-2-oxoethyl]amino]phenoxy]ethoxy]-n-[2-(acetyloxymethoxy)-2-oxoethyl]-4-methylanilino]acetate Chemical compound CC(=O)OCOC(=O)CN(CC(=O)OCOC(C)=O)C1=CC=C(C)C=C1OCCOC1=CC(C2=C3C=C(F)C(=O)C=C3OC3=CC(OCOC(C)=O)=C(F)C=C32)=CC=C1N(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O QOMNQGZXFYNBNG-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 208000002352 blister Diseases 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 230000001609 comparable effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 230000004941 influx Effects 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 229960004873 levomenthol Drugs 0.000 description 2
- 229930007503 menthone Natural products 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- -1 plasters Substances 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 239000005871 repellent Substances 0.000 description 2
- 230000002940 repellent Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000004528 spin coating Methods 0.000 description 2
- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 description 2
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 description 1
- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 description 1
- MDVYIGJINBYKOM-UHFFFAOYSA-N 3-[[5-Methyl-2-(1-methylethyl)cyclohexyl]oxy]-1,2-propanediol Chemical compound CC(C)C1CCC(C)CC1OCC(O)CO MDVYIGJINBYKOM-UHFFFAOYSA-N 0.000 description 1
- WAIGPJMZARQZDX-UHFFFAOYSA-N 4-(dimethylamino)-4-oxobutanoic acid Chemical compound CN(C)C(=O)CCC(O)=O WAIGPJMZARQZDX-UHFFFAOYSA-N 0.000 description 1
- CTMTYSVTTGVYAW-FRRDWIJNSA-N 5-[(1r,2s,5r)-5-methyl-2-propan-2-ylcyclohexyl]oxy-5-oxopentanoic acid Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)CCCC(O)=O CTMTYSVTTGVYAW-FRRDWIJNSA-N 0.000 description 1
- 101100350964 Arabidopsis thaliana PANS1 gene Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- JMDGNEGWOURLQJ-UHFFFAOYSA-N CC(c1ccc(CCCC2)c2c1)NCc(cc1)ccc1OC(F)F Chemical compound CC(c1ccc(CCCC2)c2c1)NCc(cc1)ccc1OC(F)F JMDGNEGWOURLQJ-UHFFFAOYSA-N 0.000 description 1
- 101150076566 CMR1 gene Proteins 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 241001340526 Chrysoclista linneella Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- WEEGYLXZBRQIMU-WAAGHKOSSA-N Eucalyptol Chemical compound C1C[C@H]2CC[C@]1(C)OC2(C)C WEEGYLXZBRQIMU-WAAGHKOSSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 208000004454 Hyperalgesia Diseases 0.000 description 1
- 208000035154 Hyperesthesia Diseases 0.000 description 1
- 206010020853 Hypertonic bladder Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- NFLGAXVYCFJBMK-UHFFFAOYSA-N Menthone Chemical compound CC(C)C1CCC(C)CC1=O NFLGAXVYCFJBMK-UHFFFAOYSA-N 0.000 description 1
- BLILOGGUTRWFNI-UHFFFAOYSA-N Monomenthyl succinate Chemical compound CC(C)C1CCC(C)CC1OC(=O)CCC(O)=O BLILOGGUTRWFNI-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 101100047461 Rattus norvegicus Trpm8 gene Proteins 0.000 description 1
- 229940080309 TRPM8 agonist Drugs 0.000 description 1
- 229940123537 TRPM8 antagonist Drugs 0.000 description 1
- 102000011040 TRPV Cation Channels Human genes 0.000 description 1
- 108010062740 TRPV Cation Channels Proteins 0.000 description 1
- 102000003566 TRPV1 Human genes 0.000 description 1
- 239000005844 Thymol Substances 0.000 description 1
- 101150016206 Trpv1 gene Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- UJNOLBSYLSYIBM-WISYIIOYSA-N [(1r,2s,5r)-5-methyl-2-propan-2-ylcyclohexyl] (2r)-2-hydroxypropanoate Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)[C@@H](C)O UJNOLBSYLSYIBM-WISYIIOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000005466 alkylenyl group Chemical group 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 230000001166 anti-perspirative effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003213 antiperspirant Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000008376 breath freshener Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 229960005233 cineole Drugs 0.000 description 1
- 230000003749 cleanliness Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000002781 deodorant agent Substances 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 230000001999 effect on insects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- HHVOOJDLCVOLKI-VWLOTQADSA-N methyl (2S)-2-(dibenzylamino)-3-(1H-indol-3-yl)propanoate Chemical compound C=1C=CC=CC=1CN([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)OC)CC1=CC=CC=C1 HHVOOJDLCVOLKI-VWLOTQADSA-N 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 231100000017 mucous membrane irritation Toxicity 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 208000020629 overactive bladder Diseases 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 201000005825 prostate adenocarcinoma Diseases 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 239000008257 shaving cream Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000012192 staining solution Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 125000004354 sulfur functional group Chemical group 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 102000042565 transient receptor (TC 1.A.4) family Human genes 0.000 description 1
- 108091053409 transient receptor (TC 1.A.4) family Proteins 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
- A23C13/00—Cream; Cream preparations; Making thereof
- A23C13/12—Cream preparations
- A23C13/125—Cream preparations in powdered, granulated or solid form
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
- A23G9/00—Frozen sweets, e.g. ice confectionery, ice-cream; Mixtures therefor
- A23G9/32—Frozen sweets, e.g. ice confectionery, ice-cream; Mixtures therefor characterised by the composition containing organic or inorganic compounds
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/88—Taste or flavour enhancing agents
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/03—Organic compounds
- A23L29/035—Organic compounds containing oxygen as heteroatom
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/03—Organic compounds
- A23L29/045—Organic compounds containing nitrogen as heteroatom
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/03—Organic compounds
- A23L29/055—Organic compounds containing sulfur as heteroatom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/42—Amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
- A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4946—Imidazoles or their condensed derivatives, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4986—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with sulfur as the only hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/69—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing fluorine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q17/02—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings containing insect repellants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/004—Aftersun preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q5/00—Preparations for care of the hair
- A61Q5/02—Preparations for cleaning the hair
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q5/00—Preparations for care of the hair
- A61Q5/12—Preparations containing hair conditioners
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/84—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/64—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/16—Nitrogen-containing compounds
- C08K5/20—Carboxylic acid amides
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/16—Nitrogen-containing compounds
- C08K5/34—Heterocyclic compounds having nitrogen in the ring
- C08K5/3412—Heterocyclic compounds having nitrogen in the ring having one nitrogen atom in the ring
- C08K5/3432—Six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/16—Nitrogen-containing compounds
- C08K5/34—Heterocyclic compounds having nitrogen in the ring
- C08K5/3442—Heterocyclic compounds having nitrogen in the ring having two nitrogen atoms in the ring
- C08K5/3462—Six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/36—Sulfur-, selenium-, or tellurium-containing compounds
- C08K5/45—Heterocyclic compounds having sulfur in the ring
-
- D—TEXTILES; PAPER
- D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
- D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
- D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
- D06M13/322—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing nitrogen
- D06M13/35—Heterocyclic compounds
- D06M13/355—Heterocyclic compounds having six-membered heterocyclic rings
-
- D—TEXTILES; PAPER
- D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
- D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
- D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
- D06M13/322—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing nitrogen
- D06M13/402—Amides imides, sulfamic acids
-
- D—TEXTILES; PAPER
- D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
- D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
- D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
- D06M13/322—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing nitrogen
- D06M13/402—Amides imides, sulfamic acids
- D06M13/408—Acylated amines containing fluorine atoms; Amides of perfluoro carboxylic acids
-
- D—TEXTILES; PAPER
- D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
- D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
- D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
- D06M13/322—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing nitrogen
- D06M13/402—Amides imides, sulfamic acids
- D06M13/418—Cyclic amides, e.g. lactams; Amides of oxalic acid
-
- D—TEXTILES; PAPER
- D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
- D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
- D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
- D06M13/322—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing nitrogen
- D06M13/402—Amides imides, sulfamic acids
- D06M13/432—Urea, thiourea or derivatives thereof, e.g. biurets; Urea-inclusion compounds; Dicyanamides; Carbodiimides; Guanidines, e.g. dicyandiamides
-
- D—TEXTILES; PAPER
- D21—PAPER-MAKING; PRODUCTION OF CELLULOSE
- D21H—PULP COMPOSITIONS; PREPARATION THEREOF NOT COVERED BY SUBCLASSES D21C OR D21D; IMPREGNATING OR COATING OF PAPER; TREATMENT OF FINISHED PAPER NOT COVERED BY CLASS B31 OR SUBCLASS D21G; PAPER NOT OTHERWISE PROVIDED FOR
- D21H17/00—Non-fibrous material added to the pulp, characterised by its constitution; Paper-impregnating material characterised by its constitution
- D21H17/03—Non-macromolecular organic compounds
- D21H17/05—Non-macromolecular organic compounds containing elements other than carbon and hydrogen only
- D21H17/07—Nitrogen-containing compounds
-
- D—TEXTILES; PAPER
- D21—PAPER-MAKING; PRODUCTION OF CELLULOSE
- D21H—PULP COMPOSITIONS; PREPARATION THEREOF NOT COVERED BY SUBCLASSES D21C OR D21D; IMPREGNATING OR COATING OF PAPER; TREATMENT OF FINISHED PAPER NOT COVERED BY CLASS B31 OR SUBCLASS D21G; PAPER NOT OTHERWISE PROVIDED FOR
- D21H17/00—Non-fibrous material added to the pulp, characterised by its constitution; Paper-impregnating material characterised by its constitution
- D21H17/03—Non-macromolecular organic compounds
- D21H17/05—Non-macromolecular organic compounds containing elements other than carbon and hydrogen only
- D21H17/09—Sulfur-containing compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
- A61K2800/24—Thermal properties
- A61K2800/244—Endothermic; Cooling; Cooling sensation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/74—Biological properties of particular ingredients
- A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
Definitions
- the invention relates to novel modulators of the cold menthol receptor TRPM8, a method for modulating the TRPM8 receptor using these modulators; the use of modulators to induce coldness; as well as the objects and means manufactured using these modulators.
- the cold menthol receptor TRPM8 (also known as Cold Membrane Receptor (CMR) 1) belongs to the family of "Transient Receptor Potential Ion Channels", is specifically expressed in a special group of neurons and forms pores in the cell membrane (each 4 units accumulate to form a tetramer), which selectively allow Ca 2+ ions to pass through.
- the protein has 6 transmembrane domains and a cytoplasmic C and N terminus. This receptor is stimulated by low temperatures (preferably 10-25 ° C) and a signal transduction occurs, which is interpreted by the nervous system as a feeling of cold.
- the receptor was first described as a cold receptor in several publications in 2002 ( Peier AM et al. A TRP channel that senses cold stimuli and menthol. Cell.
- Cooling compounds such as menthol have long played an important role in the flavor and fragrance industry to create an association with freshness and cleanliness.
- the compound menthol has been shown to act as a natural modulator of the TRPM8 receptor ( McKemy DD, Molecular Pain 1, 2005, 16 ; McKemy DD, Nature 416, 2002, 52-58 ; Peier AM, Cell 108, 2002, 705-715 ; Dhaka A., Annu. Rev. Neurosci. 29, 2006, 135-161 ).
- the application of menthol activates TRPM8, causing a Ca 2+ influx into the cold-sensitive neurons.
- the electrical signal thus generated is ultimately perceived as a feeling of cold.
- Excessive menthol concentrations lead to irritation and an anesthetic effect.
- the object of the present invention was therefore to identify new substances which lead to a modulation of the TRPM8 receptor, which can be used as alternatives to the previously known modulators.
- Such compounds should be particularly suitable for applications in the field of cosmetics (eg hair care, skin care, oral care), nutrition (feed / food), textiles, OTC products (eg burn ointment), pharmaceuticals (eg tumor treatment, bladder weakness), packaging or suitable as an insecticide or repellent.
- TRPM8 transient receptor potential cation channel subfamily M member 8.
- TRPP8 LTRPC6, CMR1, MGC2849, transient receptor potential cation channel subfamily M member 8.
- all designations are included.
- all functional modifications of the receptor such as in particular splice variants, isoforms such as e.g. TRPM8 CRA_a, TRPM8 CRA_b and all analog receptors from different organisms such as humans, mice, rats.
- the nucleotide or amino acid sequences of the various receptors are known per se and are stored in sequence databases. E.g. the sequence information for hTRPM8 is entered under the number NM_024080.
- a “modulator” within the meaning of the invention represents a compound which can act as an agonist and / or antagonist of the TRPM8 receptor in vivo and / or in vitro.
- Suitable modulators can act either only as an antagonist or agonist or both as an antagonist and as an agonist.
- an agonistic or an antagonistic effect can be established depending on the particular selected modulator concentration.
- An “agonist” is a compound that mediates activation of the TRPM8 receptor, that is, induces a Ca 2+ influx into the cold-sensitive neurons and thus conveys a feeling of cold.
- An “antagonist”, on the other hand, is a compound that can counteract this activation of the TRPM8 receptor.
- a first object of the invention relates to a method for in-vitro or in-vivo modulation of the cold menthol receptor TRPM8, in particular the human TRPM8 receptor, the receptor being brought into contact with at least one compound selected from polynuclear organic compounds which modulate the permeability of these cells for Ca 2+ ions in a cellular activity test, in particular under standard conditions, using cells which recombinantly express the human TRPM8 receptor.
- standard conditions are understood to mean an activity test carried out with HEK293 cells which have been transformed with human TRPM8 and are loaded with calcium-sensitive dye (such as, for example, Fluo-4AM, ie Fluo-4-acetoxymethyl ester), subsequent addition of the Test compound and detection of the color change, the test being carried out at 37 ° C; such as. described in Example 3, below, or in Behrendt et al (2004) loc. cit.).
- calcium-sensitive dye such as, for example, Fluo-4AM, ie Fluo-4-acetoxymethyl ester
- the ring groups and bridging groups can optionally carry substituents which are selected from keto groups, -OH, -SH, -CN, -NO 2 , -C 1-6 -alkyl, or C 2-4 -alkenyl, whereby in the alkyl - Or alkenyl groups, one or more H atoms can be replaced by halogen, such as F, Cl, Br or J.
- derivatives are particularly included in the context of the invention, which allow coupling of the specifically disclosed substances to solid carriers; a large selection of corresponding linkers / spacer groups is known to the person skilled in the art.
- the derivatization can take place before the coupling to a solid phase or only through the coupling.
- the invention also relates to the use of a modulator for the TRPM8 receptor, the modulator being as defined above, as an active component of a pharmaceutical agent.
- the invention further relates to the use of a modulator for the TRPM8 receptor, the modulator being as defined above, for the treatment of prostate carcinomas, for the treatment of bladder weakness or in pain therapy.
- the invention further relates to the use of a modulator for the TRPM8 receptor, the modulator being as defined above, as an insect repellent or insecticide.
- Another object of the invention relates to the use of a modulator for the TRPM8 receptor, the modulator being as defined above, for inducing a feeling of cold in textiles.
- the substances can be associated with the textile in a wide variety of ways: e.g. by spin coating, printing, in the form of microencapsulation, direct incorporation into the textile material (e.g. extrusion), covalent coupling of suitable derivatives of the modulators (via suitable spacer / linker groups, with the help of which the molecule is reversibly or irreversibly bound to the packaging material) .
- suitable working methods are known to the person skilled in the art.
- Such agents contain, in addition to the usual components for the respective agent, an effective amount of at least one modulator according to the invention.
- Effective in this context means a concentration of the modulator which is sufficient to convey the desired effect, such as pharmacological effect, or sensory effect such as the olfactory cold effect, when the agent is applied (eg application to the skin).
- the compounds according to the invention can be combined with other known active ingredients, in particular also those with a comparable effect.
- these can be combined with known cooling compounds, e.g. Menthol, menthone, N-ethyl-p-menthane carboxamide (WS-3), N-2,3-trimethyl-2-isopropylbutanamide (WS-23), menthyl lactate (Frescolat® ML), menthone glycerol acetal (Frescolat® MGA), mono- menthyl succinate (Physcool ®), mono-menthyl glutarate, O-menthyl glycerine, menthyl N, N-dimethyl succinamate can be combined.
- known cooling compounds e.g. Menthol, menthone, N-ethyl-p-menthane carboxamide (WS-3), N-2,3-trimethyl-2-isopropylbutanamide (WS-23), menthyl lactate (Frescolat®
- the invention also relates to textile products, such as e.g. Shirts, pants, socks, towels, equipped (especially superficially) with at least one connection according to the above definition.
- the invention furthermore relates to packaging materials which are associated with at least one compound as defined above.
- the starting point for cloning the human TRPM8 receptor is an LnCaP cDNA library.
- LnCaP cDNA library This is, for example, commercially available (e.g. BioChain, Hayward, USA) or can be produced from the androgen-sensitive human prostate adenocarcinoma cell line LnCaP (e.g. ATCC, CRL1740 or ECACC, 89110211) using standard kits.
- the human TRPM8 gene isolated in this way was used to produce the plnd_M8 plasmid, its construction by the plasmid map according to Figure 2 is illustrated.
- the TRPM8 gene can also be produced synthetically.
- HEK293 cell line As a test cell system, stably transfected HEK293 cell line was produced with the human TRPM8 DNA (see above plasmid plnd-M8). Preference is given to HEK293, which offers the possibility of inducing TRPM8 expression by means of tetracycline via the plasmid introduced.
- test substances are used in triplicates in concentrations of 0.1-200 ⁇ M in the assay. Usually the compounds are kept ready in DMSO solutions and diluted down to a maximum DMSO concentration of 2% for the assay.
- EC50 values determined for modulators according to the invention are summarized in Table 2 below ⁇ b> Table 2: ⁇ /b> Activity of test substances on the human receptor TRPM8 # Activity TRPM8 EC50 1 0.4 2 2 3 2 4th 2.5 5 2.5 6th 3.5 7th 4th 8th 5 9 10 10 11 10 12 10 13 10 14th 20th 15th 20th 16 25th 17th 50 18th 100 19th 100
- a mouthwash of the following composition is made: Ethanol 95% 177mL Sorbitol 70% 250 g TRPM8 agonist according to Table 2 as a 1% solution in ethanol 50mL Peppermint oil, 0.30 g Methyl salicylate 0.64 g Eucalyptol 0.922 g Thymol 0.639 g Benzoic acid 1.50 g Pluronic ® F127 nonionic surfactant 5.00 g Sodium saccharin 0.60 g Sodium citrate 0.30 g citric acid 0.10 g Water qs 1 liter
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Birds (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Food Science & Technology (AREA)
- Nutrition Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Textile Engineering (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Urology & Nephrology (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Pain & Pain Management (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Rheumatology (AREA)
- Inorganic Chemistry (AREA)
- Emergency Medicine (AREA)
- Cosmetics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
- Die Erfindung betrifft neuartige Modulatoren des Kälte-Menthol-Rezeptors TRPM8, Verfahren zur Modulation des TRPM8-Rezeptors unter Verwendung dieser Modulatoren; die Verwendung der Modulatoren zur Induktion von Kältegefühl; sowie die unter Verwendung dieser Modulatoren hergestellten Gegenstände und Mittel.
- Der Kälte-Menthol-Rezeptor TRPM8 (auch bezeichnet als Cold-Membrane Receptor (CMR)1) gehört zur Familie der "Transient Receptor Potential Ion Channels", wird spezifisch in einer speziellen Gruppe von Neuronen exprimiert und bildet in der Zellmembran Poren aus (jeweils 4 Einheiten lagern sich dabei zu einem Tetramer zusammen), die selektiv Ca2+ Ionen passieren lassen. Das Protein weist 6 Transmembrandomänen auf und einen cytoplasmatischen C- sowie N-Terminus. Durch niedrige Temperaturen (bevorzugt 10-25°C) wird dieser Rezeptor stimuliert, es kommt zu einer Signaltransduktion, die vom Nervensystem als Kältegefühl interpretiert wird. Der Rezeptor ist erstmals 2002 als Kälterezeptor in mehreren Publikationen beschrieben worden (Peier AM et al, .A TRP channel that senses cold stimuli and menthol.Cell. 2002 Mar 8;108(5):705-15; McKemy DD et al. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002 Mar 7;416(6876):52-8; Zuker CS. Neurobiology: a cool ion channel.Nature. 2002 Mar 7;416(6876):27-8)
- Kühlende Verbindungen, wie z.B. Menthol, spielen bereits seit langem eine wichtige Rolle in der Geschmacks- und Riechstoffindustrie, um eine Assoziation mit Frische und Sauberkeit zu erzeugen. Für die Verbindung Menthol ist gezeigt worden, dass sie als ein natürlicher Modulator des Rezeptors TRPM8 wirkt (McKemy D.D., Molecular Pain 1, 2005, 16; McKemy D.D., Nature 416, 2002, 52-58; Peier A.M., Cell 108, 2002, 705-715; Dhaka A., Annu. Rev. Neurosci. 29, 2006, 135-161). Durch Applikation von Menthol wird TRPM8 aktiviert, wodurch ein Ca2+-Einstrom in die Kälte-sensitiven Neuronen bewirkt wird. Das dadurch erzeugte elektrische Signal wird schließlich als Kältegefühl wahrgenommen. Überhöhte Menthol-Konzentrationen führen zu Irritation und einer anästhetischen Wirkung. Darüber hinaus sind in verschiedenen Publikationen Mentholderivate mit ähnlicher Wirkung beschrieben worden (British Patent
1971#1315761 WO 2004/026840 ), WS-23 oder in der PatentanmeldungWO 2007/019719 aufgeführte Verbindungen. - Weitere Wirkungen von Substanzen, die den TRPM8 Rezeptor bzw. seine Insektenanaloga modulieren, sind eine Repellentwirkung auf Insekten (
WO 2002/015692 ;WO 2004/000023 ,US 2004/0028714 ), sowie Aktivität in der Antitumortherapie (z.B. eine Beeinflussung von Prostatatumoren), Aktivität bei der Behandlung von inflammatorischen Schmerzen / Hyperalgesie und eine Wirkung als TRPM8 Antagonisten in der Therapie von Blasensyndrom bzw. überaktiver Blase (Beck B. Cell Calcium, 41, 2007, 285-294; Levine J.D. Biochim. Biophys. Acta, Mol. Basis Dis. 1772, 2007, 989-1003; Mukerji G., BMC Urology 6, 2006, 6;US 2003/0207904 ;US 2005/6893626 , Dissertation Behrendt H.J. 2004, Universität Bochum; Lashinger E.S.R. Am. J. Physiol. Renal Physiol. Am J Physiol Renal Physiol. 2008 Jun 18. [Epub ahead of print]; PMID: 18562636). - Viele der bisher gefundenen Modulatoren von TRPM8 weisen jedoch Mängel in Bezug auf Wirkstärke, Wirkdauer, Haut-/Schleimhautreizung, Geruch, Geschmack, Löslichkeit und /oder Flüchtigkeit auf.
- Aufgabe der vorliegenden Erfindung war es daher, neue Substanzen zu identifizieren, die zu einer Modulation des TRPM8 Rezeptors führen, welche als Alternativen zu den bisher bekannten Modulatoren einsetzbar sind. Solche Verbindungen sollten sich insbesondere auch für Anwendungen im Bereich Kosmetik (z.B. hair care, skin care, oral care), Ernährung (feed/food), Textil, OTC-Produkte (z.B. Brandsalbe), Pharmaka (z.B. Tumorbehandlung, Blasenschwäche), Verpackungen oder als Insektizid bzw. Repellent eignen.
-
-
Figur 1 zeigt (a) die mRNA-Sequenz bzw. (b) die davon abgeleitete Aminosäuresequenz des hTRPM8 Rezeptors gemäß Sequenzdatenbank-Eintrag NM 024080. -
Figur 2 zeigt die Vektorkarte des mit hTRPM8 kodierenden Plasmids plnd_M8, welches zur Transfektion der HEK293 Zellen verwendet wurde. - In der Literatur gibt es verschiedene Synonyme für "TRPM8": TRPP8, LTRPC6, CMR1, MGC2849, transient receptor potential cation channel subfamily M member 8. Im Sinne der vorliegenden Erfindung sind alle Bezeichnungen mit umfasst. Mit umfasst sind auch alle funktionalen Modifikationen des Rezeptors, wie insbesondere Splicevarianten, Isoformen, wie z.B. TRPM8 CRA_a, TRPM8 CRA_b und alle analogen Rezeptoren aus verschiedenen Organismen, wie Mensch, Maus, Ratte. Die Nukleotid- bzw. Aminosäuresequenzen der verschiedenen Rezeptoren sind an sich bekannt und in Sequenzdatenbanken hinterlegt. So ist z.B. die Sequenzinformation für hTRPM8 unter der Nummer NM_024080 eingetragen.
- Ein "Modulator" im Sinne der Erfindung stellt eine Verbindung dar, die als Agonist und/oder Antagonist des TRPM8-Rezeptors in vivo und/oder in vitro wirken kann.
- Geeignete Modulatoren können dabei entweder nur als Antagonist oder Agonist oder sowohl als Antagonist als auch als Agonist agieren. Dabei können sich insbesondere eine agonistische oder eine antagonistische Wirkung in Abhängigkeit von der jeweiligen gewählten Modulatorkonzentration einstellen.
- Ein "Agonist" ist dabei eine Verbindung, welche eine Aktivierung des TRPM8-Rezeptors vermittelt, also einen Ca2+ -Einstrom in die kälte-sensitiven Neuronen induziert und damit ein Kältegefühl vermittelt. Ein "Antagonist" ist dagegen eine Verbindung, welche dieser Aktivierung des TRPM8-Rezeptors entgegenwirken kann.
- Die erfindungsgemäßen Mediatoren können ihre Wirkung dadurch ausüben, dass sie reversibel oder irreversibel, spezifisch oder unspezifisch an ein TRPM8 Rezeptormolekül binden. Gewöhnlich erfolgt die Bindung nicht-kovalent über ionische und/oder nichtionische, wie z.B. hydrophobe, Wechselwirkungen mit dem Rezeptormolekül. "Spezifisch" umfasst dabei sowohl ausschließliche Wechselwirkung mit einem oder mehreren verschiedenen TRPM8 Rezeptormolekülen (wie z.B. TRPM8-Molekülen verschiedenen Ursprungs oder verschiedenen Isoformen). "Unspezifisch" ist dagegen eine Wechselwirkung des Modulators mit mehreren verschiedenen Rezeptormolekülen unterschiedlicher Funktion und/oder Sequenz, wobei sich jedoch als Folge eine gewünschte agonistische und/oder antagonistische Modulation (wie oben beschrieben) des TRPM8 Rezeptors feststellen lässt.
- Ein erster Gegenstand der Erfindung betrifft ein Verfahren zur in-vitro oder in-vivo Modulation des Kälte-Menthol-Rezeptors TRPM8, insbesondere des humanen TRPM8 Rezeptors, wobei man den Rezeptor mit wenigstens einer Verbindung in Kontakt bringt, die ausgewählt ist unter mehrkernigen organischen Verbindungen, welche in einem zellulären Aktivitätstest, insbesondere unter Standardbedingungen, unter Verwendung von Zellen, welche den humanen TRPM8-Rezeptor rekombinant exprimieren, die Permeabilität dieser Zellen für Ca2+ Ionen modulieren.
- Unter "Standardbedingungen" versteht man in diesem Zusammenhang einen Aktivitätstest, durchgeführt mit HEK293-Zellen, welche transformiert wurden mit humanem TRPM8 und beladen sind mit Calcium-sensitivem Farbstoff (wie z.B. Fluo-4AM, d.h. Fluo-4-Acetoxymethylester), anschließende Zugabe der Testverbindung und Nachweis der Farbänderung, wobei Versuchsdurchführung bei 37 °C erfolgt; wie z.B. beschrieben in Beispiel 3, unten, oder bei Behrendt et al (2004) a.a.O).
- Insbesondere umfasst dabei die modulierende Verbindung wenigstens zwei 4- bis 7-gliedrige Ringe, die unabhängig voneinander carbo- oder hetrerocyclisch, mono- oder polycyclisch sind, und wobei wenigstens zwei dieser Ringe gegebenenfalls kondensiert oder spiro-verknüpft sein können. Andere nichtlimitierende Beispiele geeigneter Ring-Verknüpfungen umfassen chemische Einfachbindungen zwischen Ringkohlenstoff- und/oder Ringheteroatomen, über 2 bis 6-gliedrige Kohlenstoffbrückengruppen, wobei einzelne C-Atome durch Heteroatome, wie N, O oder S, ersetzt sein können. Außerdem können die Ringgruppen und Brückengruppen ggf. Substituenten tragen, die ausgewählt sind unter Ketogruppen, -OH, -SH, -CN, -NO2, -C1-6-Alkyl, oder C2-4-Alkenyl, wobei in den Alkyl- oder Alkenylgruppen ein oder mehrere H-Atome durch Halogen, wie F, Cl, Br oder J ersetzt sein können.
- Carbocyclische Ringe umfassen dabei 4, 5, 6 oder 7 Kohlenstoffatome; heterocyclische Ringe umfassen neben den Ringkohlenstoffatomen 1 bis 3 gleiche oder verschiedene Ring-Heteroatome, wie O, N und S-Atome. Die Ringe können dabei unabhängig voneinander gesättigt, ein- oder mehrfach ungesättigt, wie z.B. aromatische Ringe, sein.
- Die erfindungsgemäß eingesetzten Modulator wirken dabei auf die zelluläre Ca2+-lonen-Permeabilität agonistisch oder antagonistisch. Insbesondere ist der Modulator wenigstens eine Verbindung, ausgewählt unter Verbindungen der folgenden Formeln 1 bis 19 gemäß folgender Tabelle 1
Tabelle 1: Erfindungsgemäße Modulatoren 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 - So sind beispielsweise bekannt:
- Verbindung 1 unter CAS Nummer: 99602-94-5 (3R-cis-Form)
- Verbindung 2 unter CAS Nummer: 165753-08-2
- Verbindung 3 unter CAS Nummer: 338771-57-6
- Verbindung 4 unter CAS Nummer: 878942-21-3
- Verbindung 5 unter CAS Nummer: 748783-13-3
- Die abgewandelten Formen oder Derivate werden auch als funktionale Analoga oder funktional äquivalente Verbindungen bezeichnet, wenn sie weiterhin die gewünschte biologische Aktivität (Rezeptor TRPM8 Modulation) zeigen.
- Weiterhin sind besonders Derivate im Sinne der Erfindung mit umfasst, die eine Kopplung der konkret offenbarten Substanzen an feste Träger erlauben; eine große Auswahl an entsprechenden Linkern/Spacer-Gruppen ist dem Fachmann bekannt. Die Derivatisierung kann dabei vor der Kopplung an eine feste Phase oder erst durch die Kopplung erfolgen.
- Ein weiterer Gegenstand der Erfindung betrifft die Verwendung eines Modulators, insbesondere Agonisten, für den TRPM8-Rezeptor, wobei der Modulator wie oben definiert ist, zur Induktion von Kältegefühl, insbesondere topisch, d.h. cutan oder oral, bei Mensch und/oder Tier. Eine "Induktion von Kältegefühl" liegt vor, wenn die Verbindung im oben beschriebenen zellulären Aktivitätstest einen agonistischen Effekt auf hTRPM8 zeigt.
- Ein weiterer Gegenstand der Erfindung betrifft die Verwendung eines Modulators für den TRPM8-Rezeptor, wobei der Modulator wie oben definiert ist, als aktiven Bestandteil eines pharmazeutischen Mittels.
- Ein weiterer Gegenstand der Erfindung betrifft die Verwendung eines Modulators für den TRPM8-Rezeptor, wobei der Modulator wie oben definiert ist, zur Behandlung von Prostatakarzinomen, zur Behandlung von Blasenschwäche oder in der Schmerztherapie.
- Ein weiterer Gegenstand der Erfindung betrifft die Verwendung eines Modulators für den TRPM8-Rezeptor, wobei der Modulator wie oben definiert ist, als Insekten-Repellent oder Insektizid.
- Ein weiterer Gegenstand der Erfindung betrifft die Verwendung eines Modulators für den TRPM8-Rezeptor, wobei der Modulator wie oben definiert ist, zur Induktion eines Kältegefühls bei Verpackungen (z.B. aus Papier oder Kunststoff in verschiedensten Verarbeitungsformen (wie z.B. Fasern, Geweben, Formteilen), wobei sich das Kältegefühl insbesondere bei Kontakt mit dem Verpackungsmaterial bemerkbar macht. Dabei können die Substanzen in unterschiedlichster Art mit dem Verpackungsmaterial assoziiert sein: z.B. durch Spincoating, Aufdrucken, in Form von Mikroverkapselung, direkte Einarbeitung in das Verpackungsmaterial (z.B. extrudieren), kovalente Kopplung von geeigneten Derivaten der Modulatoren (über geeignete Spacer/Linker-Gruppen, mit deren Hilfe das Molekül reversibel oder irreversibel an das Verpackungsmaterial gebunden wird). Geeignete Arbeitsweisen sind dem Fachmann bekannt.
- Ein weiterer Gegenstand der Erfindung betrifft die Verwendung eines Modulators für den TRPM8-Rezeptor, wobei der Modulator wie oben definiert ist, zur Induktion eines Kältegefühls bei Textilien. Dabei können die Substanzen in unterschiedlichster Art mit dem Textil assoziiert sein: z.B. durch Spincoating, Aufdrucken, in Form von Mikroverkapselung, direkte Einarbeitung in das Textilmaterial (z.B. extrudieren), kovalente Kopplung von geeigneten Derivaten der Modulatoren (über geeignete Spacer/Linker-Gruppen, mit deren Hilfe das Molekül reversibel oder irreversibel an das Verpackungsmaterial gebunden wird). Geeignete Arbeitsweisen sind dem Fachmann bekannt.
- Ein weiterer Gegenstand der Erfindung betrifft Stoffe per se gemäß obiger Definition zur Verwendung als Mediator, insbesondere Agonisten und/oder Antagonisten, des TRPM8 Rezeptors.
Ein weiterer Gegenstand der Erfindung betrifft Mittel, enthaltend wenigstens eine Verbindung nach obiger Definition. Insbesondere sind solche Mittel ausgewählt unter - a) pharmazeutischen Mitteln, wie Antitumormittel, Mittel zur Behandlung von Erkrankungen der Blase, Schmerzmittel;
- b) Nahrungsmitteln, wie Eis, Mousse, Creme, Getränke, Süßwaren,
- c) Mundpflegemitteln, wie Zahnpasta, Mundwasser, Kaugummi, Atemerfrischungsmittel
- d) Haut-, oder Haarpflegemitteln, wie Sonnencreme, Sonnenbrandcreme, Lotionen, Shampoos, Pflaster, Mundwasser, Lotionen, Rasiercreme, Conditioner, Gesichtsreiniger, Seifen, Badeöle und Badeschäume, Antitranspirationsmittel, desodorierende Mittel,
- e) Insektenrepellents, Insektiziden.
- Derartige Mittel enthalten neben für das jeweilige Mittel jeweils üblichen Bestandteilen eine wirksame Menge wenigstens eines erfindungsgemäßen Modulators. "Wirksam" bedeutet in diesem Zusammenhang eine Konzentration des Modulators, die ausreicht, um bei Applikation des Mittels (z.B. Auftragung auf die Haut) den gewünschten Effekt, wie z.B. pharmakologischen Effekt, oder sensorischen Effekt wie z.B. den olfaktorischen Kälteeffekt zu vermitteln.
- Gegebenenfalls können die erfindungsgemäßen Verbindungen mit weiteren bekannten Wirkstoffen, insbesondere auch solchen mit vergleichbarer Wirkung, kombiniert werden. Beispielsweise können diese mit bekannten kühlenden Verbindungen, wie z.B. Menthol, Menthon, N-Ethyl-p-menthancarboxamid (WS-3), N-2,3-Trimethyl-2-isopropylbutanamid (WS-23), Menthyllactat (Frescolat® ML), Menthonglycerinacetal (Frescolat® MGA), Mono-menthylsuccinat (Physcool ®), Mono-menthyl glutarat, O-Menthyl Glycerin, Menthyl-N,N-dimethylsuccinamat kombiniert werden.
- Gegenstand der Erfindung sind weiterhin Textilprodukte, wie z.B. Hemden, Hosen, Socken, Handtücher, ausgerüstet (insbesondere oberflächlich) mit wenigstens einer Verbindung nach obiger Definition.
- Gegenstand der Erfindung sind weiterhin Verpackungsmaterialien, welche mit wenigstens einer Verbindung nach obiger Definition assoziiert sind.
- Die Erfindung wird nun anhand folgender nicht-limitierender Ausführungsbeispiele beschrieben.
- Ausgangspunkt für die Klonierung des humanen TRPM8 Rezeptors ist eine LnCaP cDNA-Bank. Diese ist beispielsweise kommerziell erhältlich (z. B. Firma BioChain, Hayward, USA) oder aus der androgensensitiven humanen Prostata-Adenokarzinomzelllinie LnCaP (z.B. ATCC, CRL1740 oder ECACC, 89110211) unter Verwendung von Standardkits herstellbar.
- Die kodierende TRPM8 Sequenz (vgl
Fig.1A ; sowie http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=109689694) kann unter Verwendung von Standardmethoden PCR-amplifiziert und kloniert werden. Das so isolierte humane TRPM8 Gen wurde zur Herstellung des Plasmids plnd_M8 verwendet, dessen Konstruktion durch die Plasmidkarte gemäßFigur 2 veranschaulicht wird. - Alternativ dazu kann das TRPM8 Gen auch synthetisch hergestellt werden.
- Als Testzellsystem wurde mit der humanen TRPM8 DNA (vgl obiges Plasmid plnd-M8) stabil transfizierte HEK293 Zelllinie hergestellt. Bevorzugt wird dabei HEK293 die über das eingebrachte Plasmid die Möglichkeit zur Induktion der TRPM8-Expression mittels Tetrazyklin bietet.
- Methoden zur Herstellung geeigneter Testzellsysteme sind dem Fachmann bekannt. So kann man die Herstellung der erfindungsgemäß verwendeten Zellen den Angaben in Behrendt H.J. et al.,, Br. J. Pharmacol. 141, 2004, 737-745 oder der Dissertation von Behrendt "Vergleichende funktionale Untersuchungen des Hitze-Capsaicin-Rezeptors (TRPV1) und des Kälte-Menthol-Rezeptors (TRPM8) in rekombinanten und nativen Zellssystemen", zugänglich unter http://www-brs.ub.ruhr-uni-bochum.de/netahtml/HSS/Diss/BehrendtHansJoerg/diss.pdf entnehmen. Auf die Offenbarung dieser Druckschriften wird ausdrücklich Bezug genommen.
- Es wird ein Test, vergleichbar mit dem bereits in der Literatur beschrieben Test von Behrendt H.J. et al., Br. J. Pharmacol. 141, 2004, 737-745, durchgeführt. Die Agonisierung bzw. Antagonisierung des Rezeptors kann mittels eines Ca2+-sensitiven Farbstoffs (z.B. FURA, Fluo-4 etc.) quantifiziert werden. Agonisten bewirken alleine eine Zunahme des Ca2+-Signals; Antagonisten bewirken in Gegenwart von z.B. Menthol eine Reduzierung des Ca2+-Signals (jeweils detektiert über den Farbstoff Fluo-4, der durch Ca2+ andere Fluoreszenzeigenschaften hat).
- Zunächst wird in an sich bekannter Weise in Zellkulturflaschen eine frische Kultur transformierter HEK-Zellen hergestellt. Die Testzellen HEK293-TRPM8 werden mittels Trypsin von den Zellkulturflaschen abgelöst und 40.000 Zellen/well werden mit 100 µl Medium in 96-Lochplatten (Greiner # 655948 Poly-D-Lysin-beschichtet) ausgesät. Zur Induktion des Rezeptors TRPM8 wird dem Wachstumsmedium Tetrazyklin beigemischt (DMEM/HG, 10% FCS tetrazyklinfrei, 4 mM L-Glutamin, 15 µg/ml Blasticidin, 100 µg/ml Hygromycin B, 1 µg/ml Tetrazyklin). Am darauffolgenden Tag werden die Zellen mit Fluo-4AM Farbstoff beladen und der Test wird durchgeführt. Dazu wird wie folgt vorgegangen:
- Zugabe von je 100 µl/well Färbelösung Ca-4 Kit (RB 141, Molecular Devices) zu je 100 µl Medium (DMEM/HG, 10% FCS tetrazyklinfrei, 4 mM L-Glutamin, 15 µg/ml Blasticidin, 100 µg/ml Hygromycin B, 1 µg/ml Tetrazyklin)
- Inkubation im Brutschrank, 30 Minuten / 37°C / 5% CO2, 30 Minuten / RT
- Vorbereitung der Testsubstanzen (unterschiedliche Konzentrationen in 200 µl HBSS-Puffer), sowie von Positivkontrollen (unterschiedliche Konzentrationen von Menthol, Icilin bzw. lonomycin in 200 µl HBSS-Puffer) und Negativkontrollen (nur 200 µl HBSS-Puffer)
- Zugabe der Testsubstanzen in Mengen von 50 µl/well und Messung der Fluoreszenzänderung (z.B. im Assaygerät FLIPR, Molecular Devices oder NovoStar, BMG) bei 485 nm Anregung, 520 nm Emission, und Auswertung der Wirkstärke der verschiedenen Substanzen/Konzentrationen und Bestimmung der EC50-Werte
- Die Testsubstanzen werden in Triplikaten in Konzentrationen von 0,1 - 200 µM im Assay eingesetzt. Normalerweise werden die Verbindungen in DMSO-Lösungen bereitgehalten und für den Assay auf eine maximale DMSO-Konzentration von 2% herunterverdünnt.
- Die ermittelten EC50-Werte erfindungsgemäßer Modulatoren sind in folgender Tabelle 2 zusammengefasst
Tabelle 2: Aktivität von Testsubstanzen auf den human Rezeptor TRPM8 # Activität TRPM8 EC50 1 0,4 2 2 3 2 4 2,5 5 2,5 6 3,5 7 4 8 5 9 10 10 10 11 10 12 10 13 10 14 20 15 20 16 25 17 50 18 100 19 100 - Die Auswertung zeigt überraschenderweise, dass erfindungsgemäß erstmalig Agomisten von TRPM8 bereitgestellt werden konnten, welche sich strukturell von bisher bekannten Agonisten, wie (-) Menthol, Icilin und anderen von Behrendt H.J. et al.,in Br. J. Pharmacol. 141, 2004, 737-745 (vgl dortige Tabelle 1) beschriebenen Modulatoren signifikant unterscheiden und zudem teilweise bessere Aktivitäten als (-) Menthol zeigen, bzw. vergleichbar stark wirken wie Icilin.
- Ein Mundwasser folgender Zusammensetzung wird hergestellt:
Ethanol 95% 177mL Sorbit 70% 250 g TRPM8 Agonist gemäß von Tab.2 als 1% Lösung im Ethanol 50mL Pfefferminzöl, 0.30 g Methylsalicylat 0.64 g Eucalyptol 0.922 g Thymol 0.639 g Benzoesäure 1.50 g Pluronic ® F127 nichtionisches Tensid 5.00 g Natrium-Saccharin 0.60 g Natriumcitrat 0.30 g Zitronensäure 0.10 g Wasser q.s. 1 Liter - Zur Herstellung eines Mundwassers werden die oben beschriebenen Komponenten in den angegebenen Mengen miteinander vermischt.
- Auf die Offenbarung der hierin zitierten Literaturstellen wird hiermit ausdrücklich Bezug genommen.
- Weitere Ausführungsformen der Erfindung:
2. Verfahren zur in-vitro oder in-vivo Modulation des Kälte-Menthol-Rezeptors TRMP8, wobei man den Rezeptor mit wenigstens einer Verbindung in Kontakt bringt, die ausgewählt ist unter mehrkernigen organischen Verbindungen, welche in einem zellulären Aktivitätstest unter Verwendung von Zellen, welche den humanen TRPM8-Rezeptor rekombinant exprimieren, die Permeabilität dieser Zellen für Ca2+ Ionen modulieren.
3. Verfahren nach Ausführungsform 1, wobei die modulierende Verbindung wenigstens zwei 4- bis 7-gliedrige Ringe ausweist, die unabhängig voneinander carbo- oder hetrerocyclisch, mono- oder polycyclisch sind, und wobei wenigstens zwei dieser Ringe gegebenenfalls kondensiert sein können.
4. Verfahren nach Ausführungsform1 oder 2, wobei der Modulator auf die zelluläre Ca2+-Ionen-Permeabilität agonistisch oder antagonistisch wirkt.
5. Verfahren nach einem der vorhergehenden Ausführungsformen, wobei der Modulator eine Verbindung ist, ausgewählt unter Verbindungen der Formeln 1 bis 191 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
7. Verwendung eines Modulators für den TRPM8-Rezeptor, wobei der Modulator gemäß einem der Ausführungsformen 1 bis 4 definiert ist, als aktiven Bestandteil eines pharmazeutischen Mittels.
8. Verwendung eines Modulators für den TRPM8-Rezeptor, wobei der Modulator gemäß einem der Ausführungsformen 1 bis 4 definiert ist, zur Behandlung von Prostatakarzinomen, zur Behandlung von Blasenschwäche oder in der Schmerztherapie.
9. Verwendung eines Modulators für den TRPM8-Rezeptor, wobei der Modulator gemäß einem der Ausführungsformen 1 bis 4 definiert ist, als Insekten-Repellent oder Insektizid.
10. Verwendung eines Modulators für den TRPM8-Rezeptor, wobei der Modulator gemäß einem der Ausführungsformen 1 bis 4 definiert ist, zur Induktion eines Kältegefühls in einer Verpackung
11. Verwendung eines Modulators für den TRPM8-Rezeptor, wobei der Modulator gemäß einem der Ausführungsformen 1 bis 4 definiert ist, zur Induktion eines Kältegefühls in einem Textil
12. Stoff gemäß der Definition nach einem der Ausführungsformen 1 bis 4 zur Verwendung als Mediator des TRMP8 Rezeptors.
13. Mittel enthaltend wenigstens eine Verbindung nach einem der Ausführungsformen 1 bis 4.
14. Mittel nach Ausführungsform 12, ausgewählt unter - a) pharmazeutischen Mitteln, wie Antitumormittel, Mittel zur Behandlung von Erkrankungen der Blase, Schmerzmittel;
- b) Nahrungsmitteln, wie Eis, Mousse, Creme, Getränke, Süßwaren,
- c) Mundpflegemitteln, wie Zahnpasta, Mundwasser, Kaugummi,
- d) Haut- oder Haarpflegemitteln, wie Sonnencreme, Sonnenbrandcreme, Lotionen, Shampoos, Pflaster,
- e) Insektenrepellents, Insektiziden.
16. Verpackungsmaterial, welches mit wenigstens einer Verbindung nach einem der Ausführungsformen 1 bis 4 assoziiert ist.
Claims (12)
- Verfahren zur in-vitro Modulation des Kälte-Menthol-Rezeptors TRPM8, wobei man den Rezeptor mit wenigstens einer Verbindung in Kontakt bringt, die ausgewählt ist unter den Verbindungen der Formeln
- Verfahren nach Anspruch 1, wobei der Modulator auf die zelluläre Ca2+-Ionen-Permeabilität agonistisch wirkt.
- Verwendung eines Modulators für den TRPM8-Rezeptor, wobei der Modulator gemäß Anspruch 1 definiert ist, zur nicht-therapeutischen Induktion von Kältegefühl bei Mensch und/oder Tier.
- Verwendung eines Modulators für den TRPM8-Rezeptor der obigen Formel 6, 7 oder 8 als aktiven Bestandteil eines pharmazeutischen Mittels.
- Modulator für den TRPM8-Rezeptor der obigen Formel 6, 7 oder 8 zur Verwendung bei der Behandlung von Prostatakarzinomen, zur Behandlung von Blasenschwäche oder in der Schmerztherapie.
- Verwendung eines Modulators für den TRPM8-Rezeptor, wobei der Modulator gemäß Anspruch 1 definiert ist, als Insekten-Repellent oder Insektizid.
- Verwendung eines Modulators für den TRPM8-Rezeptor, wobei der Modulator gemäß Anspruch 1 definiert ist, zur Induktion eines Kältegefühls in einer Verpackung oder einem Textil.
- Verbindung der obigen Formel 6, 7 oder 8 zur Verwendung als Medikament.
- Mittel enthaltend im Gemisch mit üblichen Bestandteilen wenigstens eine Verbindung der obigen Formel 6, 7 oder 8.
- Mittel nach Anspruch 9, ausgewählt untera) pharmazeutischen Mitteln, wie Antitumormittel, Mittel zur Behandlung von Erkrankungen der Blase, Schmerzmittel;b) Nahrungsmitteln, wie Eis, Mousse, Creme, Getränke, Süßwaren,c) Mundpflegemitteln, wie Zahnpasta, Mundwasser, Kaugummi,d) Haut- oder Haarpflegemitteln, wie Sonnencreme, Sonnenbrandcreme, Lotionen, Shampoos, Pflaster,e) Insektenrepellents, Insektiziden.
- Textilprodukte, wie Hemden, Hosen, Socken, Handtücher, ausgerüstet mit wenigstens einer Verbindung nach Anspruch 1.
- Verpackungsmaterial, welches mit wenigstens einer Verbindung der obigen Formel 6, 7 oder 8 assoziiert ist.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP08162997 | 2008-08-26 | ||
PCT/EP2009/061019 WO2010026094A1 (de) | 2008-08-26 | 2009-08-26 | Nachweis und verwendung niedermolekularer modulatoren des kälte-menthol-rezeptors trpm8 |
EP09782234.0A EP2349239B1 (de) | 2008-08-26 | 2009-08-26 | Nachweis und verwendung niedermolekularer modulatoren des kälte-menthol-rezeptors trpm8 |
EP16175305.8A EP3115045B1 (de) | 2008-08-26 | 2009-08-26 | Nachweis und verwendung niedermolekularer modulatoren des kälte-menthol-rezeptors trpm8 |
Related Parent Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP09782234.0A Division EP2349239B1 (de) | 2008-08-26 | 2009-08-26 | Nachweis und verwendung niedermolekularer modulatoren des kälte-menthol-rezeptors trpm8 |
EP16175305.8A Division-Into EP3115045B1 (de) | 2008-08-26 | 2009-08-26 | Nachweis und verwendung niedermolekularer modulatoren des kälte-menthol-rezeptors trpm8 |
EP16175305.8A Division EP3115045B1 (de) | 2008-08-26 | 2009-08-26 | Nachweis und verwendung niedermolekularer modulatoren des kälte-menthol-rezeptors trpm8 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP3698779A1 true EP3698779A1 (de) | 2020-08-26 |
Family
ID=41119517
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP09782234.0A Active EP2349239B1 (de) | 2008-08-26 | 2009-08-26 | Nachweis und verwendung niedermolekularer modulatoren des kälte-menthol-rezeptors trpm8 |
EP16175305.8A Active EP3115045B1 (de) | 2008-08-26 | 2009-08-26 | Nachweis und verwendung niedermolekularer modulatoren des kälte-menthol-rezeptors trpm8 |
EP16175302.5A Active EP3103447B1 (de) | 2008-08-26 | 2009-08-26 | Nachweis und verwendung niedermolekularer modulatoren des kälte-menthol-rezeptors trpm8 |
EP19214768.4A Pending EP3698779A1 (de) | 2008-08-26 | 2009-08-26 | Nachweis und verwendung niedermolekularer modulatoren des kälte-menthol-rezeptors trpm8 |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP09782234.0A Active EP2349239B1 (de) | 2008-08-26 | 2009-08-26 | Nachweis und verwendung niedermolekularer modulatoren des kälte-menthol-rezeptors trpm8 |
EP16175305.8A Active EP3115045B1 (de) | 2008-08-26 | 2009-08-26 | Nachweis und verwendung niedermolekularer modulatoren des kälte-menthol-rezeptors trpm8 |
EP16175302.5A Active EP3103447B1 (de) | 2008-08-26 | 2009-08-26 | Nachweis und verwendung niedermolekularer modulatoren des kälte-menthol-rezeptors trpm8 |
Country Status (7)
Country | Link |
---|---|
US (2) | US8710096B2 (de) |
EP (4) | EP2349239B1 (de) |
JP (3) | JP5591238B2 (de) |
CN (4) | CN102137660B (de) |
CA (4) | CA2937195C (de) |
ES (3) | ES2828974T3 (de) |
WO (1) | WO2010026094A1 (de) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102137660B (zh) | 2008-08-26 | 2014-08-13 | 巴斯夫欧洲公司 | 冷薄荷醇受体trpm8的低分子量调节剂的检测和用途 |
DE102010002558A1 (de) | 2009-11-20 | 2011-06-01 | Symrise Ag | Verwendung physiologischer Kühlwirkstoffe und Mittel enthaltend solche Wirkstoffe |
AU2011323245B2 (en) * | 2010-11-05 | 2016-01-21 | Senomyx, Inc. | Compounds useful as modulators of TRPM8 |
EP2497458A1 (de) | 2011-03-08 | 2012-09-12 | B.R.A.I.N. Biotechnology Research And Information Network AG | Kleinmolekülige Modulatoren des Kälte- und Mentholrezeptors TRMP8 |
EP2758041B1 (de) | 2011-09-20 | 2021-01-13 | Basf Se | Niedermolekulare modulatoren des kälte-menthol-rezeptors trpm8 und deren verwendung |
US20130251647A1 (en) | 2011-09-20 | 2013-09-26 | Basf Se | Low molecular weight modulators of the cold menthol receptor trpm8 and use thereof |
JP2013155141A (ja) * | 2012-01-31 | 2013-08-15 | Mikimoto Pharmaceut Co Ltd | 化粧料 |
US20130273619A1 (en) | 2012-04-16 | 2013-10-17 | Basf Se | Process for the Preparation of (3E, 7E)-Homofarnesol |
EP2931225B1 (de) * | 2012-12-12 | 2021-03-31 | Symrise AG | Kühlende zubereitungen |
JP6882144B6 (ja) * | 2012-12-12 | 2021-06-23 | シムライズ アーゲー | 組成物および化粧品組成物 |
EP3212162A2 (de) * | 2014-10-31 | 2017-09-06 | Avent, Inc. | Verfahren und artikel zur hemmung von blasenkontraktionen |
KR101624339B1 (ko) | 2014-12-16 | 2016-05-25 | 남우현 | Trpm8 저온수용체 단백질 활성화가 우수한 탈모방지 샴푸 |
US10568852B2 (en) | 2015-05-22 | 2020-02-25 | Helmholtz Zentrum Munchen - Deutsches Forschungszentrum Fur Gesundheit Und Umwelt (Gmbh) | Combination compositions and their use in methods for treating obesity and obesity-related disorders |
BR112018006471B1 (pt) * | 2015-10-01 | 2024-02-27 | Senomyx, Inc | Composto, composição, método de modular o membro de melastina do canal potencial do receptor transitório 8 (trpm8), método de modular a sensação de resfrescância de uma composição e método de induzir uma sensação de refrescância em um ser humano ou animal |
EP3589276B9 (de) | 2017-07-26 | 2024-01-17 | TGX Soft Chew, LLC | Stärkefreier weicher kausnack für veterinärmedizinische anwendungen |
JP7231617B2 (ja) * | 2017-08-31 | 2023-03-01 | ビーエーエスエフ ソシエタス・ヨーロピア | 生理学的冷涼活性成分の使用、及びそのような活性成分を含む組成物 |
WO2022105986A1 (de) | 2020-11-17 | 2022-05-27 | Symrise Ag | Neue kühlstoffe und zubereitungen, die diese enthalten |
WO2023143741A1 (de) | 2022-01-28 | 2023-08-03 | Symrise Ag | Neue kühlstoffe und zubereitungen, die diese enthalten |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1315761A (en) | 1970-12-23 | 1973-05-02 | Ibm | Digital data processing systems |
WO2002015692A1 (en) | 2000-08-24 | 2002-02-28 | Givaudan Sa | Composition having insect repellent characteristics |
US20030207904A1 (en) | 2002-05-02 | 2003-11-06 | Wei Edward T. | 1,2,3,6-tetrahydropyrimidine-2-one compositions and therapeutic methods therewith for pain and inflammation |
WO2004000023A1 (en) | 2002-06-21 | 2003-12-31 | Givaudan Sa | Insect repellents |
WO2004026840A1 (en) | 2002-09-18 | 2004-04-01 | Unilever Plc | Tetrahydropyrimidine-2-one derivatives and their uses |
WO2007019719A1 (en) | 2005-08-15 | 2007-02-22 | Givaudan Sa | Cooling compounds |
WO2007080109A1 (en) * | 2006-01-16 | 2007-07-19 | Bayer Healthcare Ag | Substituded benzyloxy-phenylmethylurea derivatives |
Family Cites Families (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SU636236A1 (ru) | 1976-05-25 | 1978-12-05 | Институт Биоорганической Химии Ан Белорусской Сср | Производные 8-аза-16-оксагонана, обладающие противоспалительным действием и способ их получени |
SU704082A1 (ru) | 1978-07-05 | 1989-10-23 | Институт биоорганической химии АН БССР | Производные 8,16-диазагонана, обладающие противовоспалительной активностью и мембранозащитным действием |
RU704083C (ru) | 1978-07-05 | 1993-10-30 | Институт биоорганической химии АН БССР | Производные D-гомо-8-азагонана, обладающие противовоспалительной, мембраностабилизирующей и антикоагул ционной активностью |
SU776048A1 (ru) * | 1979-06-05 | 1983-09-23 | Институт Бисорганической Химии Ан Бсср | Производные 8-аза-16-оксагона-17-онов, про вл ющие противовоспалительную,мембраностабилизирующую и антифибринолитическую активность,и способ их получени |
CH651445A5 (en) | 1982-07-28 | 1985-09-30 | Ciba Geigy Ag | Composition and method for the selective control of weeds in transplanted rice or rice which is sown in water |
WO1991001801A1 (en) * | 1989-08-01 | 1991-02-21 | Kanebo, Ltd. | Microcapsule, treatment liquid containing microcapsules, and textile structure having microcapsules stuck thereto |
JP3394596B2 (ja) * | 1994-05-23 | 2003-04-07 | 日本テトラパック株式会社 | 包装容器 |
WO1998058905A1 (fr) * | 1997-06-25 | 1998-12-30 | Yamanouchi Pharmaceutical Co., Ltd. | Nouveaux derives d'amidrazone a action antifongicide |
NO306533B1 (no) | 1998-04-21 | 1999-11-22 | Gunnar Volden | Insektmiddel |
JP2000302760A (ja) * | 1999-02-17 | 2000-10-31 | Hokuriku Seiyaku Co Ltd | 2−メルカプトキノリン誘導体 |
EP1301458B1 (de) | 2000-06-23 | 2015-09-09 | California Institute Of Technology | Synthese funktionalisierter und nicht funktionalisierter olefine durch cross und ringschliessende metathese |
US7247741B2 (en) | 2005-01-21 | 2007-07-24 | Ptc Therapeutics, Inc. | Acetylamino benzoic acid compounds and their use for nonsense suppression and the treatment of disease |
DE10234876A1 (de) * | 2002-07-25 | 2004-02-05 | Bayer Cropscience Gmbh | 4-Trifluormethylpyrazolyl substituierte Pyridine und Pyrimidine |
DE10259619A1 (de) * | 2002-12-18 | 2004-07-08 | Metagen Pharmaceuticals Gmbh | Verwendung einer TRPM8 aktivierenden Substanz zur Tumorbehandlung |
US6893626B2 (en) | 2003-02-18 | 2005-05-17 | Edward T. Wei | Compositions for TRP-M8 binding and radioreceptor methods therewith |
US7169377B2 (en) * | 2003-10-15 | 2007-01-30 | Wei Edward T | Radioligands for the TRP-M8 receptor and methods therewith |
BRPI0508556A (pt) * | 2004-03-08 | 2007-08-07 | Wyeth Corp | moduladores de canal iÈnico |
CN1964988A (zh) * | 2004-04-08 | 2007-05-16 | 詹森药业有限公司 | 犬的冷和薄荷醇敏感受体1 |
WO2005099711A1 (en) * | 2004-04-13 | 2005-10-27 | Icagen, Inc. | Polycyclic pyrimidines as potassium ion channel modulators |
US20050250836A1 (en) * | 2004-05-03 | 2005-11-10 | Pfizer Inc | Inhibitors of checkpoint kinases (Wee1 and Chk1) |
EP1802600A1 (de) | 2004-10-13 | 2007-07-04 | Bayer HealthCare AG | Substituierte 4-benzyloxy-phenylmethylamid-derivate als kälte-menthol-rezeptor-1 (cmr-1) -antagonisten für die behandlung von urologischen erkrankungen |
EP1868685A2 (de) * | 2005-03-18 | 2007-12-26 | onepharm GmbH | 11ß-HYDROXYSTEROIDDEHYDROGENASEN |
WO2007017093A1 (en) * | 2005-08-04 | 2007-02-15 | Bayer Healthcare Ag | Substituted 2-benzyloxy-benzoic acid amide derivatives |
EP1940791B1 (de) | 2005-10-25 | 2009-09-16 | Givaudan SA | Organische verbindungen |
EP1986622B1 (de) * | 2006-02-15 | 2013-10-02 | Dendreon Corporation | Kleinmolekülige modulatoren der trp-p8-aktivität |
GB0615136D0 (en) * | 2006-07-29 | 2006-09-06 | Univ Edinburgh | Induction of analgesia in neuropathic pain |
EP1913976A1 (de) | 2006-10-18 | 2008-04-23 | Symrise GmbH & Co. KG | N-alpha-(Menthancarbonyl)aminosäureamide und deren Verwendung als physiologische Kühlwirkstoffe |
EP1958627A3 (de) | 2007-01-04 | 2010-09-01 | Symrise GmbH & Co. KG | Verwendung bestimmter Menthyl-3-oxocarbonsäureester als physiologisch wirksame Kühlsubstanzen |
EP2033688B1 (de) | 2007-08-20 | 2012-10-17 | Symrise AG | Oxalsäurederivate und deren Verwendung als physiologische Kühlwirkstoffe |
US20110124649A1 (en) * | 2007-11-09 | 2011-05-26 | The Johns Hopkins University | Inhibitors of human methionine aminopeptidase 1 and methods of treating disorders |
WO2010010435A2 (en) | 2008-07-22 | 2010-01-28 | Glenmark Pharmaceutical S.A. | Fused oxazole and thiazole derivatives as trpms modulators |
CN102137660B (zh) | 2008-08-26 | 2014-08-13 | 巴斯夫欧洲公司 | 冷薄荷醇受体trpm8的低分子量调节剂的检测和用途 |
-
2009
- 2009-08-26 CN CN200980133390.7A patent/CN102137660B/zh active Active
- 2009-08-26 CN CN201710396933.0A patent/CN107375284B/zh active Active
- 2009-08-26 CA CA2937195A patent/CA2937195C/en active Active
- 2009-08-26 EP EP09782234.0A patent/EP2349239B1/de active Active
- 2009-08-26 ES ES16175305T patent/ES2828974T3/es active Active
- 2009-08-26 CA CA3044178A patent/CA3044178C/en active Active
- 2009-08-26 CA CA2937196A patent/CA2937196C/en active Active
- 2009-08-26 US US13/060,323 patent/US8710096B2/en active Active
- 2009-08-26 EP EP16175305.8A patent/EP3115045B1/de active Active
- 2009-08-26 ES ES16175302T patent/ES2828975T3/es active Active
- 2009-08-26 CN CN201410336374.0A patent/CN104147016B/zh active Active
- 2009-08-26 EP EP16175302.5A patent/EP3103447B1/de active Active
- 2009-08-26 WO PCT/EP2009/061019 patent/WO2010026094A1/de active Application Filing
- 2009-08-26 JP JP2011524370A patent/JP5591238B2/ja active Active
- 2009-08-26 ES ES09782234.0T patent/ES2659421T3/es active Active
- 2009-08-26 CN CN202010795118.3A patent/CN111803478B/zh active Active
- 2009-08-26 EP EP19214768.4A patent/EP3698779A1/de active Pending
- 2009-08-26 CA CA2734682A patent/CA2734682C/en active Active
-
2014
- 2014-03-12 US US14/206,182 patent/US9346823B2/en active Active
- 2014-07-29 JP JP2014153389A patent/JP5795107B2/ja active Active
-
2015
- 2015-08-11 JP JP2015158967A patent/JP5956036B2/ja active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1315761A (en) | 1970-12-23 | 1973-05-02 | Ibm | Digital data processing systems |
WO2002015692A1 (en) | 2000-08-24 | 2002-02-28 | Givaudan Sa | Composition having insect repellent characteristics |
US20040028714A1 (en) | 2000-08-24 | 2004-02-12 | Philippe Blondeau | Composition having insect repellent characteristics |
US20030207904A1 (en) | 2002-05-02 | 2003-11-06 | Wei Edward T. | 1,2,3,6-tetrahydropyrimidine-2-one compositions and therapeutic methods therewith for pain and inflammation |
WO2004000023A1 (en) | 2002-06-21 | 2003-12-31 | Givaudan Sa | Insect repellents |
WO2004026840A1 (en) | 2002-09-18 | 2004-04-01 | Unilever Plc | Tetrahydropyrimidine-2-one derivatives and their uses |
WO2007019719A1 (en) | 2005-08-15 | 2007-02-22 | Givaudan Sa | Cooling compounds |
WO2007080109A1 (en) * | 2006-01-16 | 2007-07-19 | Bayer Healthcare Ag | Substituded benzyloxy-phenylmethylurea derivatives |
Non-Patent Citations (19)
Title |
---|
"863 POSTER A phase II study of BAY 43-9006 (sorafenib) in patients with androgen-independent prostate cancer (AIPC)", EUROPEAN JOURNAL OF CANCER. SUPPLEMENT, PERGAMON, OXFORD, GB, vol. 3, no. 2, 1 October 2005 (2005-10-01), pages 248, XP027683901, ISSN: 1359-6349, [retrieved on 20051001] * |
A. WEIL: "Conservation of functional and pharmacological properties in the distantly related temperature sensors TRPV1 and TRPM8", MOLECULAR PHARMACOLOGY, 1 January 2005 (2005-01-01), XP055050932, ISSN: 0026-895X, DOI: 10.1124/mol.105.012146 * |
BECK B., CELL CALCIUM, vol. 41, 2007, pages 285 - 294 |
BEHRENDT H.J. ET AL., BR. J. PHARMACOL., vol. 141, 2004, pages 737 - 745 |
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 748783-13-3 |
DHAKA A., ANNU. REV. NEUROSCI., vol. 29, 2006, pages 135 - 161 |
FURRER S.M., CHEM. PERCEPT., vol. 1, 2008, pages 119 - 126 |
LASHINGER E.S.R., AM. J. PHYSIOL. RENAL PHYSIOL. AM J PHYSIOL RENAL PHYSIOL., 18 June 2008 (2008-06-18) |
LEVINE J.D., BIOCHIM. BIOPHYS. ACTA, MOL. BASIS DIS., vol. 1772, 2007, pages 989 - 1003 |
MCKEMY D.D., MOLECULAR PAIN, vol. 1, 2005, pages 16 |
MCKEMY D.D., NATURE, vol. 416, 2002, pages 52 - 58 |
MCKEMY DD ET AL.: "Identification of a cold receptor reveals a general role for TRP channels in thermosensation", NATURE, vol. 416, no. 6876, 7 March 2002 (2002-03-07), pages 52 - 8, XP055572652, DOI: 10.1038/nature719 |
MUKERJI G., BMC UROLOGY, vol. 6, 2006, pages 6 |
PEIER A.M., CELL, vol. 108, 2002, pages 705 - 715 |
PEIER AM ET AL.: "A TRP channel that senses cold stimuli and menthol", CELL, vol. 108, no. 5, 8 March 2002 (2002-03-08), pages 705 - 15, XP002246274, DOI: 10.1016/S0092-8674(02)00652-9 |
WALTER DANNEKER ET AL: "Bildung von N.a -Diorganylbenzylammen aus der als Lithiumcyanat (4) identifiziert werden dimetallierten N-Benzyl-N.N'-diorganylharn- konnte, wieder aufhellten. Nach einem Tag isolierte stoffen1", ZEITSCHRIFT FÜR NATURFORSCHUNG, TEIL B: ANORGANISCHE CHEMIE,, vol. 29, no. 7-8, 1 August 1974 (1974-08-01), pages 578 - 580, XP055714551 * |
WATSON H.R., J. SOC. COSMET. CHEM., vol. 29, 1978, pages 185 - 200 |
WEI, J. PHARM. PHARMACOL., vol. 35, 1983, pages 110 - 112 |
ZUKER CS: "Neurobiology: a cool ion channel", NATURE, vol. 416, no. 6876, 7 March 2002 (2002-03-07), pages 27 - 8 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3115045B1 (de) | Nachweis und verwendung niedermolekularer modulatoren des kälte-menthol-rezeptors trpm8 | |
DE60017988T2 (de) | Anwendung von mindestens einem Hydroxystilben als Glykationshemmer | |
DE69630380T3 (de) | Neue verwendungen von thyroidhormonen oder thyroidhormon aehnliche verbindungen | |
DE69920567T2 (de) | Methode zur Verhütung des Körpergeruchs von alten Leute | |
DE60224257T2 (de) | Retinolderivate und verfahren zu deren herstellung | |
DE69815306T2 (de) | Valnoctamid-stereoisomere, eine methode zu ihrer herstellung und abtrennung und ihre anwendungen | |
JP2001010926A (ja) | 美白剤 | |
DE2505635C3 (de) | Verwendung von auf synthetischem Wege gewonnenem 2,6,10,15,19,23-Hexamethyltetracosan als Grundkomponente für Kosmetika und topiseh anzuwendende Präparate | |
DE1617705A1 (de) | Kosmetisches Mittel zur Behandlung der Haare und Kopfhaut | |
DE102022108329A1 (de) | Zusammensetzung zur Behandlung der Haut | |
Mohamed | Acid–base equilibria of diazepam and prazepam in montmorillonite suspensions | |
JPH101421A (ja) | 育毛剤 | |
JP2013040113A (ja) | フィラグリン産生促進剤 | |
JPH09241118A (ja) | 皮膚化粧料 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN PUBLISHED |
|
AC | Divisional application: reference to earlier application |
Ref document number: 2349239 Country of ref document: EP Kind code of ref document: P Ref document number: 3115045 Country of ref document: EP Kind code of ref document: P |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20210226 |
|
RBV | Designated contracting states (corrected) |
Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
17Q | First examination report despatched |
Effective date: 20231027 |